The goal of this proposal is to understand the biological and functional role of the Notch3 gene in the development of the human vascular dementia syndrome CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). CADASIL is a recently defined syndrome that is characterized by recurring subcortical ischemic episodes and migraines that eventually progress to dementia and death. The morphological characteristics of CADASIL include vascular smooth muscle degeneration and defects in the leptomeningeal and intracerebral arteries. The prevalence of CADASIL remains unknown, however it is believed to under diagnosed. Recently, the CADASIL gene has been identified as a member of the Notch gene family, Notch3. The Notch gene family has been shown to be required for normal embryonic development and is involved in neurogenesis, myogenesis and determination of cell fates. All of the mutations observed in CADASIL patients were missense mutations. To test the hypothesis that these missense mutations are sufficient to generate a mouse model of CADASIL, gene-targeted knock-in mice will be generated with the analogous mutations. It is currently unknown what effect these missense mutations have on Notch3 function. Experiments in Drosophila suggest that these mutations can lead to ligand- dependent hyperactivation. Regardless of the effects on Notch3 function, a mouse model of the vascular dementia syndrome CADASIL would be a valuable tool for examining the pathogenesis of this disease. In addition, this proposal will further our understanding of the roles for the Notch signaling pathway in development and disease in mammals.